chr9-134699909-C-T

Position:

chr9-134699909-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBS1BS2

The NM_000093.5(COL5A1):c.278C>T(p.Ala93Val) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00315 in 1,613,882 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0033 ( 8 hom. )

Consequence

COL5A1
NM_000093.5 missense, splice_region

Scores

Splicing: ADA: 0.02236

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:17

Conservation

PhyloP100: 1.31

Variant links:

Genes affected

COL5A1 (HGNC:2209): (collagen type V alpha 1 chain) This gene encodes an alpha chain for one of the low abundance fibrillar collagens. Fibrillar collagen molecules are trimers that can be composed of one or more types of alpha chains. Type V collagen is found in tissues containing type I collagen and appears to regulate the assembly of heterotypic fibers composed of both type I and type V collagen. This gene product is closely related to type XI collagen and it is possible that the collagen chains of types V and XI constitute a single collagen type with tissue-specific chain combinations. The encoded procollagen protein occurs commonly as the heterotrimer pro-alpha1(V)-pro-alpha1(V)-pro-alpha2(V). Mutations in this gene are associated with Ehlers-Danlos syndrome, types I and II. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, May 2013]

COL5A1 links:

COL5A1 (HGNC:):

COL5A1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), COL5A1. . Gene score misZ 2.0682 (greater than the threshold 3.09). Trascript score misZ 4.1823 (greater than threshold 3.09). GenCC has associacion of gene with Ehlers-Danlos syndrome, classic type, 1, arterial disorder, Ehlers-Danlos syndrome, classic type.

BP4

Computational evidence support a benign effect (MetaRNN=0.009988606).

BP6

Variant 9-134699909-C-T is Benign according to our data. Variant chr9-134699909-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 212916.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-134699909-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.002 (304/152348) while in subpopulation NFE AF= 0.00354 (241/68030). AF 95% confidence interval is 0.00318. There are 0 homozygotes in gnomad4. There are 148 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 304 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL5A1	NM_000093.5 linkuse as main transcript	c.278C>T	p.Ala93Val	missense_variant, splice_region_variant	3/66	ENST00000371817.8	NP_000084.3	P20908-1A0A024R8E5B2ZZ86Q59EE7
COL5A1	NM_001278074.1 linkuse as main transcript	c.278C>T	p.Ala93Val	missense_variant, splice_region_variant	3/66		NP_001265003.1	B2ZZ86Q59EE7
COL5A1	XM_017014266.3 linkuse as main transcript	c.278C>T	p.Ala93Val	missense_variant, splice_region_variant	3/65		XP_016869755.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
COL5A1	ENST00000371817.8 linkuse as main transcript	c.278C>T	p.Ala93Val	missense_variant, splice_region_variant	3/66	1	NM_000093.5	ENSP00000360882.3	P20908-1
COL5A1	ENST00000371820.4 linkuse as main transcript	c.278C>T	p.Ala93Val	missense_variant, splice_region_variant	3/66	2		ENSP00000360885.4	P20908-2H7BY82
COL5A1	ENST00000464187.1 linkuse as main transcript	n.700C>T		splice_region_variant, non_coding_transcript_exon_variant	4/6	2

Frequencies

GnomAD3 genomes

AF:

0.00200

AC:

304

AN:

152230

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000555

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000981

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000828

Gnomad FIN

AF:

0.00179

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00354

Gnomad OTH

AF:

0.000955

GnomAD3 exomes

AF:

0.00194

AC:

487

AN:

250912

Hom.:

AF XY:

0.00204

AC XY:

277

AN XY:

135748

show subpopulations

Gnomad AFR exome

AF:

0.000616

Gnomad AMR exome

AF:

0.000781

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000719

Gnomad FIN exome

AF:

0.00148

Gnomad NFE exome

AF:

0.00336

Gnomad OTH exome

AF:

0.00261

GnomAD4 exome

AF:

0.00327

AC:

4781

AN:

1461534

Hom.:

Cov.:

AF XY:

0.00330

AC XY:

2401

AN XY:

727040

show subpopulations

Gnomad4 AFR exome

AF:

0.000358

Gnomad4 AMR exome

AF:

0.000827

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000905

Gnomad4 FIN exome

AF:

0.00169

Gnomad4 NFE exome

AF:

0.00392

Gnomad4 OTH exome

AF:

0.00326

GnomAD4 genome

AF:

0.00200

AC:

304

AN:

152348

Hom.:

Cov.:

AF XY:

0.00199

AC XY:

148

AN XY:

74508

show subpopulations

Gnomad4 AFR

AF:

0.000553

Gnomad4 AMR

AF:

0.000980

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000829

Gnomad4 FIN

AF:

0.00179

Gnomad4 NFE

AF:

0.00354

Gnomad4 OTH

AF:

0.000945

Alfa

AF:

0.00324

Hom.:

Bravo

AF:

0.00179

TwinsUK

AF:

0.00351

AC:

ALSPAC

AF:

0.00389

AC:

ESP6500AA

AF:

0.00113

AC:

ESP6500EA

AF:

0.00314

AC:

ExAC

AF:

0.00190

AC:

231

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00322

EpiControl

AF:

0.00284

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:17

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Feb 15, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	COL5A1: BP4, BS1 -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

not specified

Benign:4

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 25, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 05, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 21, 2023	- -

Ehlers-Danlos syndrome, classic type, 1

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Mar 15, 2022	- -

Marfan syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University Hospital Muenster

May 11, 2022

ACMG categories: BS2,BP1,BP6 -

Fibromuscular dysplasia, multifocal

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Mar 15, 2022

- -

Familial thoracic aortic aneurysm and aortic dissection

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 14, 2018

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Ehlers-Danlos syndrome type 7A

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Ehlers-Danlos syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Mar 19, 2021

- -

Ehlers-Danlos syndrome, classic type

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Feb 06, 2018

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.091

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.59

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.15

T;.

Eigen

Benign

-0.49

Eigen_PC

Benign

-0.37

FATHMM_MKL

Uncertain

0.80

LIST_S2

Uncertain

0.91

D;D

M_CAP

Benign

0.012

MetaRNN

Benign

0.010

T;T

MetaSVM

Benign

-0.91

MutationAssessor

Benign

1.4

L;L

PrimateAI

Benign

0.47

PROVEAN

Benign

-1.7

N;.

REVEL

Benign

0.046

Sift

Uncertain

0.0050

D;.

Sift4G

Uncertain

0.048

D;D

Polyphen

0.0060

B;.

Vest4

0.13

MVP

0.16

MPC

0.21

ClinPred

0.016

GERP RS

3.9

Varity_R

0.039

gMVP

0.20

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.022

dbscSNV1_RF

Benign

0.28

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over